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Andrea E. Cavanna

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Subscriber: null; date: 23 October 2019

Zonisamide is a second-generation antiepileptic drug (AED) (Fig. 16.1) known with the proprietary brand name of Zonegran® (Eisai) in the UK and USA (Fig. 16.2).

Fig. 16.1 Chronology of the clinical use of zonisamide

Fig. 16.1 Chronology of the clinical use of zonisamide

Fig. 16.2 Chemical structure of zonisamide

Fig. 16.2 Chemical structure of zonisamide



  • Zonisamide 25 mg (14-tab pack).

  • Zonisamide 50 mg (56-tab pack).

  • Zonisamide 100 mg (56-tab pack).

Generic formulation

MHRA/CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):

  • Category 2: the need for continued supply of a particular manufacturer’s product should be based on clinical judgment and consultation with the patient and/or carer taking into account factors such as seizure frequency and treatment history.



Monotherapy of focal seizures with or without secondary generalization and adjunctive therapy of refractory focal seizures with or without secondary generalization.

Recommendations summarized from NICE (2012)

  • Seizure types: on referral to tertiary care (absence seizures, focal seizures, myoclonic seizures).

  • Epilepsy types: on referral to tertiary care (absence syndromes, juvenile myoclonic epilepsy, idiopathic generalized epilepsy, benign epilepsy with centrotemporal spikes, panayiotopoulos syndrome, late-onset childhood occipital epilepsy).

Dose titration



100 mg od for 14 days, then increased by 100 mg every 14 days; usual maintenance 300 mg od (max. 500 mg daily).

Adjunctive therapy

25 mg bd for 7 days, 50 mg bd for 7 days, then increased by 100 mg every 7 days; usual maintenance 300–500 mg daily, divided into 1 or 2 doses (dose to be increased every 14 days in patients who are not on carbamazepine, phenobarbital, phenytoin, or other potent inducers of cytochrome P450 enzyme CYP3A4).

Plasma levels monitoring

Although plasma levels can be measured, and a therapeutic range has been postulated (10–40 mg/L), there is little evidence base for recommending routine measurement of plasma levels in clinical practice.


  • Patients with metabolic acidosis (consider dose reduction or discontinuation if metabolic acidosis develops).

  • Patients with low body weight or poor appetite (monitor weight throughout treatment).

  • Patients with risk factors or predisposition to nephrolithiasis.

  • Elderly patients.

Adverse effects

Zonisamide can be associated with adverse effects at the level the nervous system and other systems (Table 16.1).

Table 16.1 Estimated frequency of adverse effects of zonisamide

Very common (>1 in 10 patients on zonisamide)

Nervous system

  • agitation

  • anorexia

  • ataxia

  • confusion

  • depression

  • diplopia

  • dizziness

  • drowsiness

  • irritability

  • memory problems

Other systems

Common (>1 in 100 patients on zonisamide)

Nervous system

  • fatigue

  • impaired attention

  • insomnia

  • nystagmus

  • paraesthesias

  • psychosis

  • speech disorder

  • tremor

Other systems

  • abdominal pain

  • constipation

  • diarrhoea

  • ecchymosis

  • nausea

  • peripheral oedema

  • pruritus

  • pyrexia

  • skin rash (consider withdrawal)

Uncommon (>1 in 1000 patients on zonisamide)

Nervous system

  • aggression

  • suicidal ideation

  • worsening of seizures

Other systems

  • cholecystitis and cholelithiasis

  • dyspepsia

  • hypokalaemia

  • pneumonia

  • urinary calculus and urinary tract infection

  • vomiting

Rare (>1 in 10,000 patients on zonisamide)

Nervous system

Other systems

Very rare (<1 in 10,000 patients on zonisamide)

Nervous system

  • amnesia

  • coma

  • hallucinations

  • myasthenic syndrome

  • neuroleptic malignant syndrome

Other systems

  • aspiration

  • blood disorders

  • dyspnoea

  • heat stroke

  • hepatitis

  • hydronephrosis

  • impaired sweating

  • metabolic acidosis

  • pancreatitis

  • renal failure and renal tubular acidosis

  • rhabdomyolysis

  • severe skin reactions (toxic epidermal necrolysis and Stevens–Johnson syndrome)


With AEDs

  • Exposure to zonisamide is lower in epileptic patients receiving CYP3A4-inducing agents such as phenytoin, carbamazepine, and phenobarbital. These effects are unlikely to be of clinical significance when zonisamide is added to existing therapy; however, changes in zonisamide concentrations may occur if concomitant CYP3A4-inducing antiepileptic or other medicinal products are withdrawn, dose adjusted or introduced, an adjustment of the zonisamide dose may be required.

  • Zonisamide should be used with caution in adult patients treated concomitantly with carbonic anhydrase inhibitors such as topiramate and acetazolamide, as there are insufficient data to rule out a possible pharmacodynamic interaction.

With other drugs

  • Caution is advised when starting or stopping zonisamide treatment or changing the zonisamide dose in patients who are also receiving P-gp substrates such as digoxin and quinidine.

  • If co-administration with rifampicin (a potent CYP3A4 inducer) is necessary, the patient should be closely monitored and the dose of zonisamide and other CYP3A4 substrates adjusted as needed.

With alcohol/food

There are no known specific interactions between alcohol and zonisamide and there are no specific foods that must be excluded from diet when taking zonisamide.

Special populations

Hepatic impairment

  • Initially increase dose every 14 days in moderate impairment.

  • Avoid in severe impairment.

Renal impairment

  • Initially increase dose every 14 days in moderate impairment.

  • Discontinue if renal function deteriorates.


  • There are limited data from the use of zonisamide in pregnant women and the potential risk in terms of reproductive toxicity for humans is unknown.

  • Zonisamide must not be used during pregnancy unless it is required based on the clinical condition of the patient. In such cases, the dose of zonisamide should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.

  • Zonisamide is excreted in human milk; the concentration in breastmilk is similar to maternal plasma. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from zonisamide therapy. Due to the long retention time of zonisamide in the body, breastfeeding must not be resumed until 1 month after zonisamide therapy is completed.

Behavioural and cognitive effects in patients with epilepsy

The behavioural profile of zonisamide in patients with epilepsy features specific problems, which can occur with high doses. The most commonly reported behavioural symptoms are depression, irritability, agitation, and psychosis. Cognitive deficits reported by patients treated with zonisamide mainly involve attention, concentration, and language domains (most effects occur at high doses).

Psychiatric use

Zonisamide does not have any approved indications in psychiatry. Initial findings from uncontrolled studies suggesting that zonisamide may be effective in the treatment of bipolar disorder did not find confirmation. There is preliminary evidence for possible usefulness of zonisamide in the treatment of obesity and psychotropic-associated weight gain, as well as alcohol dependence and withdrawal (Fig. 16.3).

Fig. 16.3 Level of evidence supporting the psychiatric use of zonisamide in patients with behavioural symptoms

Fig. 16.3 Level of evidence supporting the psychiatric use of zonisamide in patients with behavioural symptoms

Overall rating

Zonisamide is characterized by a few antiepileptic indications, with an acceptable interaction profile in polytherapy; it has an acceptable tolerability profile and no psychiatric uses (Table 16.2).

Table 16.2 Overall rating of zonisamide

Antiepileptic indications

Interactions in polytherapy

Behavioural tolerability

Psychiatric use

Key: ☺☺☺ = very good; ☺☺ = good; ☺ = acceptable.